This invention is directed to a process for making ketosulfone esters such as (1S)-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl isopropoxyacetate. These compounds are intermediates useful in the preparation of certain non-steroidal antiinflammatory agents, such as the compounds disclosed in U.S. Pat. No. 5,981,576 and U.S. Pat. No. 6,020,343.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
This invention encompasses a process for making a compound of Formula A 
wherein R2 is C1-6alkyl, optionally substituted with C3-6cycloalkyl, and
R3 and R4 are C1-6alkyl,
comprising: reacting pivaloyl chloride with a compound of Formula B 
a compound of Formula C 
and trialkylamine in the presence of a catalyst in a substantially non-reactive solvent to yield a compound of Formula D 
and
oxidizing the compound of Formula D to yield a compound of Formula A.
These compounds are intermediates useful in the preparation of certain non-steroidal anti-inflammatory agents.
U.S. Pat. No. 5,981,576, granted on Nov. 9, 1999 and U.S. Pat. No., 6,020,343, granted on Feb. 1, 2000 are hereby incorporated by reference in their entirety.
This invention encompasses a process for making a compound of Formula A 
wherein R2 is C1-6alkyl, optionally substituted with C3-6cycloalkyl, and
R3 and R4 are C1-6alkyl,
comprising: reacting pivaloyl chloride with a compound of Formula B 
a compound of Formula C 
and trialkylamine in the presence of a catalyst in a substantially non-reactive solvent to yield a compound of Formula D 
and
oxidizing the compound of Formula D to yield a compound of Formula A.
An embodiment of the invention encompasses the process wherein trialkylamine is triethylamine.
Another embodiment of the invention encompasses the process wherein the catalyst is 4-dimethylaminopyridine.
Another embodiment of the invention encompasses the process wherein the substantially non-reactive solvent is toluene.
Another embodiment of the invention encompasses the process wherein pivaloyl chloride is sequentially the last reagent to be added.
Another embodiment of the invention encompasses the process wherein the ratio of trialkylamine to the compound of Formula B is in the range of about 2.1 to 3.1 equivalents of trialkylamine relative to about 1 equivalent of the compound of Formula B.
Another embodiment encompasses the process wherein the ratio of pivaloyl chloride to the compound of Formula B is less than about 2.5 equivalents of pivaloyl chloride relative to about 1 equivalent of the compound of Formula B. Preferably, the equivalence ratio of pivaloyl chloride to the compound of Formula B is about 1.5 to 1.
Another embodiment encompasses the process wherein the ratio of the compound of Formula C to the compound of Formula B is at least about 1.2 equivalents of the compound of Formula C relative to about 1 equivalent of the compound of Formula B and the ratio of the catalyst to the compound of Formula B is at least about 0.3 equivalents of the catalyst relative to about 1 equivalent of the compound of Formula B.
Another embodiment of the invention encompasses the process further comprising of making the compound of Formula A at ambient temperature.
Another embodiment of the invention encompasses the process wherein conversion to the compound of Formula D is greater than about 95%.
The invention also encompasses the process further comprising of making the compound of Formula B by reacting a compound of Formula E 
with a lithiating agent and a compound of Formula F 
in a substantially non-reactive solvent at a reduced temperature to produce a compound of Formula B. The term xe2x80x9clithiating agentxe2x80x9d means for example n-butyllithium, hexyllithium and phenyllithium. Preferably, the reduced temperature is about xe2x88x9235xc2x0 C. to about xe2x88x9230xc2x0 C. Within this embodiment is encompassed this process further comprising of making the compound of Formula E by reacting a compound of Formula G 
with pyrrolidine and thionyl chloride in a substantially non-reactive solvent at a reduced temperature to produce a compound of Formula E. Preferably the reduced temperature is below about xe2x88x925xc2x0 C.
The invention also encompasses a process for making a compound of Formula A1
comprising: reacting pivaloyl chloride to a mixture of a compound of Formula B1
a compound of Formula C1
and trialkylainine in the presence of a catalyst in a substantially non-reactive solvent to yield a compound of Formula D1
and
oxidizing the compound of Formula D1 to yield a compound of Formula A1.
Within this embodiment is encompassed the process wherein trialkylamine is triethylamine.
Within this embodiment is encompassed the process wherein the catalyst is 4-dimethylaminopyridine.
Within this embodiment is encompassed the process wherein the substantially non-reactive solvent is toluene.
Within this embodiment is encompassed the process wherein the ratio of trialkylamine to the compound of Formula B1 is in the range of about 2.1 to 3.1 equivalents of trialkylamine relative to about 1 equivalent of the compound of Formula B1.
Within this embodiment is encompassed the process wherein the ratio of pivaloyl chloride to the compound of Formula B1 is less than about 2.5 equivalents of pivaloyl chloride relative to about 1 equivalent of the compound of Formula B1. Preferably, the equivalence ratio of pivaloyl chloride to the compound of Formula B1 is about 1.5 to 1.
Within this embodiment is encompassed the process wherein the ratio of the compound of Formula C1 to the compound of Formula B1 is at least about 1.2equivalents of the compound of Formula C relative to about 1 equivalent of the compound of Formula B1 and the ratio of the catalyst to the compound of Formula B1 is at least about 0.3 equivalents of the catalyst relative to about 1 equivalent of the compound of Formula B1.
Within this process is encompassed the process wherein conversion to the compound of Formula D1 is greater than about 95%.
For the purposes of this specification, the term xe2x80x9calkylxe2x80x9d means linear or branched structures containing the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means cyclic alkyl structures containing the indicated number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cycloheptyl, and the like.
The term xe2x80x9ctrialkylaminexe2x80x9d means tertiary alkyl substituted amines. The alkyl portions may contain 1 to 10 carbon atoms. Examples of trialkylamine include triethylamine, trimethylamine, ethyldimethylamine and the like.
The term xe2x80x9ccatalystxe2x80x9d means 4-dimethylaminopyridine (DMAP), pyridine or other pyridine derivatives.
The term xe2x80x9csubstantially non-reactive solventxe2x80x9d means, for example, toluene, benzene, xylene, etheral solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF), ester solvents including ethyl and isopropyl acetate, halo carbon solvents including mono or dihalo C1-4alkyl such as dichloromethane, and C6-10linear, branched or cyclic hydrocarbon solvents including hexane. Mixtures of two or more of the aforesaid solvents are also contemplated.
The term xe2x80x9cambient temperaturexe2x80x9d means about 20xc2x0 C.
The term xe2x80x9creduced temperaturexe2x80x9d means any temperature less than ambient temperature. Preferably, xe2x80x9creduced temperaturexe2x80x9d means below about 0xc2x0 C.
The compounds of the present invention are intermediates useful in the preparation of certain non-steroidal antiinflammatory agents, such as the compounds disclosed in U.S. Pat. No. 5,981,576 and U.S. Pat. No. 6,020,343. For example, the compound of Formula A1
can be used in the process described herein with diazobicyclo[5.4.0]undec-7-ene (DBU) to afford the following compound 
which is useful as a selective cyclooxygenase-2 inhibitor.
Throughout the instant application, the following abbreviations have the following meanings:
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
DBU=diazobicyclo[5.4.0]undec-7-ene
DMAP=4-Dimethylaminopyridine
IPAA=isopropyloxyacetic acid
Me=methyl
THF=tetrahydrofuran
The invention is illustrated in connection with the following generic scheme 1
Conversion of acid G to amide E (SOCl2, pyrrolidine, substantially nonreactive solvent) followed by arylation at low temperature (compound of Formula F, lithiating agent, substantially non-reactive solvent, xe2x88x9235 to xe2x88x925xc2x0 C.) provides the hydroxyketone B. Coupling of the hydroxyketone with a compound of Formula C (pivaloyl chloride, trialkylamine, catalyst, non-reactive solvent) followed by oxidation provides the ketosulfone ester A.